Activity of tumor-associated lymphoid cells at short intervals after administration of irradiated syngeneic and allogeneic tumor cells.

After a single intraperitoneal injection of irradiated tumor cells, host cells capable of responding against syngeneic tumors were detected in peritoneal exudates of mice. Although irradiation of the injected tumor prevented its overgrowth, it did not significantly alter the antigenicity of the tumor. Immunologic activities of tumor-associated host cells in the peritoneal cavity were continuously monitored, starting 48 hr after tumor administration. In vitro cell-mediated lysis of syngeneic tumors appeared as early as 3 days after irradiated tumor administration. In addition, peritoneal exudate cells from inoculated mice were capable of adoptively transferring immunity. Purification of these peritoneal exudate cells on nylon wool columns yielded a nonadherent Ig-negative lymphocyte fraction whose cytolysis was tumor-specific and T cell-associated. The macrophage-free lymphocyte fraction exhibited a higher in vitro activity against tumors than unpurified peritoneal exudates. This tumor-host system allowed the study of cells which directly interact with the tumor cells in vivo, starting shortly after tumor administration. The results reported in this paper show that tumor-associated lymphoid cells capable of mounting anti-tumor response in vivo and in vitro can be demonstrated as early as 3 days after tumor inoculation.     

Cell-autonomous cytokinin-independent growth of tobacco cells transformed by Agrobacterium tumefaciens strains lacking the cytokinin biosynthesis gene.

Mutations at the cytokinin biosynthesis locus (tmr) of Agrobacterium tumefaciens usually result in strains that induce tumors exhibiting the rooty phenotype associated with high auxin-to-cytokinin ratios. However, tobacco (Nicotiana tabacum cv Havana 425) leaf disc explants responded to tmr- mutant strain A356 by producing rapidly growing, unorganized tumors, indicating that these lines can grow in a cytokinin-independent fashion despite the absence of a functional tmr gene. Several methods have been used to characterize the physiological and cellular basis of this phenotype. The results indicate that tmr- tumors have a physiologically distinct mechanism for cytokinin-independent growth in comparison to tumors induced by wild-type bacteria. The cytokinin-independent phenotype of the tmr- transformants appears to be cell autonomous in nature: only the transformed cells and their progeny were capable of cytokinin-independent growth. Specifically, the tmr- tumors did not accumulate cytokinin, and clonal analysis indicated the tmr- transformed cells were not capable of stimulating the growth of neighboring nontransformed cells. Finally, the cytokinin-independent phenotype of the tmr- transformants was shown to be cold sensitive, whereas the wild-type tumors exhibited a cold-resistant cytokinin-independent phenotype. Potential mechanisms for this novel form of cytokinin-independent growth, including the role of the dehydrodiconiferyl alcohol glucosides found in both tumor types, are discussed.     

Activated K-ras and N-ras oncogenes in primary renal mesenchymal tumors induced in F344 rats by methyl(methoxymethyl)nitrosamine.

Administration of methyl(methoxymethyl)nitrosamine to newborn Fischer 344 rats results in the preferential induction of renal tumors arising from the mesenchymal component of the kidney. DNA from a significant proportion of these tumors was capable of transforming NIH/3T3 cells. This report describes the renal tumor model, the detection of two different ras transforming genes in the kidney tumors (the N-ras oncogene in 1 and K-ras oncogene in 10 kidney tumors) and the characterization of DNA sequences specifying the transformed phenotype.     

Effect of benz(a)pyrene and its non-carcinogenic analog 1,2-benzopyrene on the Na, K-ATPase activity of homogenates of different mouse organs and rat heart membrane preparations

The carcinogenic agent benz(a)pyrene inhibits Na, K-ATPase activity of organ homogenates where it is capable of inducing tumors. It causes no significant changes in target organ homogenates.     

Isolation, characterization, and biosynthesis of Forssman antigen in human lung and lung carcinoma

A glycolipid was isolated from normal lung and lung carcinoma tissues. This glycolipid was identified as the Forssman antigen of pentaglycosyl ceramide by means of chemical and immunological methods. The presence of this antigenic glycolipid was observed in all the tissues examined of adult and embryo lungs, and of lung tumors irrespective of histological type. The extracts of human lung and lung tumors were capable of catalyzing the synthesis of Forssman antigen from globoside.     

MC29 deletion mutants which fail to transform chicken macrophages are competent for transformation of quail macrophages.

A number of MC29 mutants with deleted myc genes have been previously characterized. Many of these mutants have been found to be defective for transformation of chicken macrophages in vitro and for tumor induction in chickens. Such mutants are capable of transforming Japanese quail macrophages in vitro and inducing a high incidence of tumors in Japanese quail. Thus, Japanese quail may contain a factor(s) capable of complementing the defective transforming proteins encoded by some deleted v-myc genes.     

A putative int domain for mouse mammary tumor virus on mouse chromosome 7 is a 5'' extension of int-2.

We extended the physical map of the mouse int-2 locus by demonstrating that the site of insertion for mouse mammary tumor virus DNA in plaque-type mammary tumors of GR mice is directly linked to int-2. An additional example of proviral integration is described in which a provirus in a presumed enhancer-insertion mode 15 kilobases upstream of the int-2 promoters is capable of activating expression of the gene at levels typical of other virally induced mammary tumors.     

ANAL CARCINOMA

Carcinoma of the anus is a rare tumor when skin tumors which may have arisen from the perianal skin are excluded. A significant proportion of anal carcinomas, exclusive of those from perianal skin, may very well have their origin from the intermediate zone of transitional epithelium and its and ducts, which would account for the different histological patterns presented by these cancers. These tumors are frequently described as of low grade malignancy and indeed some of them may be; but, the majority behave as very aggressive carcinomas, capable not only of rapid and extensive local invasion but also capable of lymph node metastasis. The treatment should be surgical and aggressive if operation is feasible.     

Differential expression of fibronectin in a rat histiocytoma: possible role of fibronectin in tumor cell adhesion

The specific role of fibronectin in tumor cells has been investigated using the transplantable histiocytic tumor line AK-5 [A. Khar (1986) J. Natl. Cancer Inst. 76, 871]. These cells, capable of growth as both ascites and solid tumors in rats, can be separated into four subpopulations by buoyant density centrifugation on Percoll. These subpopulations are shown to contain different amounts of fibronectin on the cell surface when studied by immunofluorescent staining followed by cytofluorometric analysis. Cells which contain high amounts of fibronectin can grow both as ascites and as solid tumors while those cells which contain low amounts of fibronectin cannot grow as solid tumors but can grow as ascitic tumors. Pretreatment of high-fibronectin-containing cells with anti-fibronectin antibody abolished their capacity to grow as solid tumors; however, the cells retained their capacity to grow as ascitic tumors. These results have been discussed with reference to the specific role of fibronectin in tumor-forming cells.     

New methods for direct delivery of chemotherapy for treating brain tumors

Despite advances in diagnostic imaging and drug discovery, primary malignant brain tumors remain fatal. Median survival for patients with the most severe forms is rarely past eight months. The severity of the disease and the lack of substantial improvement in patient survival demand that new approaches be explored in drug delivery to brain tumors. Recently, local delivery of chemotherapy to brain tumors has provided a way to circumvent the blood-brain barrier, allowing delivery of chemotherapy drugs directly to malignant cells in the brain. Two methods of local delivery have been developed: polymeric-controlled release and convection-enhanced delivery. Controlled release utilizes degradable or non-degradable polymers as carriers of chemotherapy; polymer implants or microparticles are implanted locally to introduce a sustained source of drug for periods of days or months. Convection-enhanced delivery employs the bulk flow of drugs dissolved in fluid, which is introduced intracranially using a catheter and pump. The convective fluid flow is capable of delivering drugs great distances within the brain, potentially treating invasive cells at a distance from the catheter infusion site. These two new delivery strategies are capable of delivering both standard chemotherapeutic drugs and new methods of anti-cancer therapy. Taken individually, or used in tandem, they represent a potential revolution in brain cancer treatment.     

The photobiology of melanocytes modulates the impact of UVA on sunlight-induced melanoma

Ultraviolet radiation is responsible for melanoma. In this review, we address the role of the different UV spectra in melanoma. The data suggest that only UVB is capable of initiating melanoma, and that both UVA and UVB are involved in the progression of the disease. The etiology of sunlight-induced melanoma may be different for chronically-exposed tumors and for those located on body surfaces with considerably less exposure. Solar signature mutations are most likely associated with the progression of chronically-exposed tumors. The unique relationship between UVA and melanocytes, and the role of melanin in photocarcinogenesis is discussed. The current state of knowledge strongly indicates that UVA, regardless of its source, is involved in melanoma and should be avoided to deter progression of incipient tumors.     

Agrobacterium mediated genetic transformation of chickpea, Cicer arietinum L.

In leaf and stem explants of chickpea, wild type strains of Agrobacteria were able to induce tumors. These tumors were capable of phytohormone independent growth. A supervirulent strain A281 was found to be most effective. Thus, using an agrobacterium R1601, which carries genes conferring supervirulent phenotype along with a plant selectable marker gene (npt II), transformed calli of chickpea were selected in the presence of 100 micrograms/ml level of kanamycin. Molecular analyses of genomic DNA from transformed calli confirmed the integration of the marker gene into chickpea genome.     

Steroid hormone receptors in MCCLX, a transplantable lactogen-dependent mammary tumor of the rat

MCCLX is a transplantable rat mammary tumor which, for sustained growth, requires the elevated levels of circulating lactogen provided by pregnancy or the implantation of an estrogen pellet. High affinity receptors for estradiol, as well as for the glucocorticoids, dexamethasone and triamcinolone acetonide and the progestin R5020 were measured in the cytosols of these tumors. Estrogen binding capacities were significantly lower in the cytosols of tumors from estrogen pellet treated animals compared with tumors from pregnant animals. Ligand exchange assays demonstrated that nuclei of tumors from estrogen-treated rats contained 3-4 times the estrogen receptors but that there was a definite decrease in total estrogen binding capacity compared with tumors from pregnant rats. It was concluded that this lactogen-dependent tumor contains steroid receptors with molecular properties similar to those of normal target tissues, including estrogen receptors capable of nuclear translocation, the levels of which are modulated by the specific growth conditions.     

Regulation of the immune response to tumor antigen. VI. Differential specificities of suppressor T cells or their products and effector T cells.

Suppressor T cells arising during the development of certain murine methylcholanthrene-induced fibrosarcomas have previously been shown capable of limiting only those effector responses generated against the homologous tumor. Thus, S1509a-induced suppressor T cells inhibit immune reactivity only to the S1509a tumor in S1509a immune mice and have no effect on the rejection of SAI tumors in SAI-immune animals. In contrast to this is the cross-reactivity of effector cells in this system, whereby animals rendered immune to either the S1509a or SAI sarcoma are equally capable of rejecting a challenge of the opposite tumor. The specificity of suppression has been further defined in the present study, which demonstrates that S1509a-induced suppressor cells can inhibit responsiveness only to the S1509a sarcoma, even in the simultaneous presence of both the S1509a and SAI tumors. Furthermore, the suppressor factor that is obtainable from suppressor T cells demonstrates a similar precise specificity in its ability to limit selectively reactivity only against the inducing tumor, regardless of the simultaneous expression of antigens on other tumors recognized by cross-reactive effector cells. These results suggest that the antigenic determinants recognized by effector and suppressor T cells are different, and may provide a model for further dissection of suppressor cell function in vivo.     

Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells

Despite the existence of tumor-specific antigens and demonstrated presence of tumor-specific immune cells, the majority of tumors manage to avoid immune-mediated destruction. Various mechanisms have been suggested for tumor evasion from immune response. One such mechanism is thought to be mediated by transforming growth factor-beta (TGF-beta), an immunosuppressive cytokine found at the site of most tumors. We demonstrate here that T-cell-specific blockade of TGF-beta signaling allows the generation of an immune response capable of eradicating tumors in mice challenged with live tumor cells. In addition, we provide mechanisms through which abrogation of TGF-beta signaling leads to the enhancement of anti-tumor immunity. Our data indicate that T-cell-specific blockade of TGF-beta signaling has strong therapeutic potential to shift the balance of the immune response in favor of anti-tumor immunity.     

Collective behavior in cancer cell populations

In recent years the argument has been made that malignant tumors represent complex dynamic and self‐organizing biosystems. Furthermore, there is increasing evidence that collective cell migration is common during invasion and metastasis of malignant tumors. Here, we argue that cancer systems may be capable of developing multicellular collective patterns that resemble evolved adaptive behavior known from other biological systems including collective sensing of environmental conditions and collective decision‐making. We present a concept as to how these properties could arise in tumors and why the emergence of such swarm‐like patterns would confer advantageous properties to the spatiotemporal expansion of tumors, and consequently, why understanding and ultimately targeting such collectivity should be of interest for basic and clinical cancer research alike.     

Gene therapy to manipulate effector T cell trafficking to tumors for immunotherapy

Strategies that generate tumor Ag-specific effector cells do not necessarily cure established tumors. We hypothesized that the relative efficiency with which tumor-specific effector cells reach the tumor is critical for therapy. We demonstrate in this study that activated T cells respond to the chemokine CCL3, both in vitro and in vivo, and we further demonstrate that expression of CCL3 within tumors increases the effector T cell infiltrate in those tumors. Importantly, we show that adenoviral gene transfer to cause expression of CCL3 within B16ova tumors in vivo increases the efficacy of adoptive transfer of tumor-specific effector OT1 T cells. We additionally demonstrate that such therapies result in endogenous immune responses to tumor Ags that are capable of protecting animals against subsequent tumor challenge. Strategies that modify the "visibility" of tumors have the potential to significantly enhance the efficacy of both vaccine and adoptive transfer therapies currently in development.     

Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody receptors codelivering CD28 costimulation

A new strategy to improve the therapeutic utility of redirected T cells for cancer involves the development of novel Ag-specific chimeric receptors capable of stimulating optimal and sustained T cell antitumor activity in vivo. Given that T cells require both primary and costimulatory signals for optimal activation and that many tumors do not express critical costimulatory ligands, modified single-chain Ab receptors have been engineered to codeliver CD28 costimulation. In this study, we have compared the antitumor potency of primary T lymphocytes expressing carcinoembryonic Ag (CEA)-reactive chimeric receptors that incorporate either TCR-zeta or CD28/TCR-zeta signaling. Although both receptor-transduced T cell effector populations demonstrated cytolysis of CEA(+) tumors in vitro, T cells expressing the single-chain variable fragment of Ig (scFv)-CD28-zeta chimera had a far greater capacity to control the growth of CEA(+) xenogeneic and syngeneic colon carcinomas in vivo. The observed enhanced antitumor activity of T cells expressing the scFv-CD28-zeta receptor was critically dependent on perforin and the production of IFN-gamma. Overall, this study has illustrated the ability of a chimeric scFv receptor capable of harnessing the signaling machinery of both TCR-zeta and CD28 to augment T cell immunity against tumors that have lost expression of both MHC/peptide and costimulatory ligands in vivo.     

FDTD analysis of a noninvasive hyperthermia system for brain tumors

ABSTRACT: BACKGROUND: Hyperthermia is considered one of the new therapeutic modalities for cancer treatment and is based on the difference in thermal sensitivity between healthy tissues and tumors. During hyperthermia treatment, the temperature of the tumor is raised to 40--4[DEGREE SIGN]C for a definite period resulting in the destruction of cancer cells. This paper investigates design, modeling and simulation of a new non-invasive hyperthermia applicator system capable of effectively heating deep seated as well as superficial brain tumors using inexpensive, simple, and easy to fabricate components without harming surrounding healthy brain tissues. METHODS: The proposed hyperthermia applicator system is composed of an air filled partial half ellipsoidal chamber, a patch antenna, and a head model with an embedded tumor at an arbitrary location. The irradiating antenna is placed at one of the foci of the hyperthermia chamber while the center of the brain tumor is placed at the other focus. The finite difference time domain (FDTD) method is used to compute both the SAR patterns and the temperature distribution in three different head models due to two different patch antennas at a frequency of 915 MHz. RESULTS: The obtained results suggest that by using the proposed noninvasive hyperthermia system it is feasible to achieve sufficient and focused energy deposition and temperature rise to therapeutic values in deep seated as well as superficial brain tumors without harming surrounding healthy tissue. CONCLUSIONS: The proposed noninvasive hyperthermia system proved suitable for raising the temperature in tumors embedded in the brain to therapeutic values by carefully selecting the systems components. The operator of the system only needs to place the center of the brain tumor at a pre-specified location and excite the antenna at a single frequency of 915 MHz. Our study may provide a basis for a clinical applicator prototype capable of heating brain tumors.     

A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy

p53 and INK4a/ARF mutations promote tumorigenesis and drug resistance, in part, by disabling apoptosis. We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16(INK4a). Hence, tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone-respond poorly to cyclophosphamide therapy in vivo. Moreover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16(INK4a), and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage. Finally, mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects. Therefore, cellular senescence contributes to treatment outcome in vivo.